Randomized, Prospective Evaluation Comparing Intensity of Lymphodepletion Before Adoptive Transfer of Tumor-Infiltrating Lymphocytes for Patients With Metastatic Melanoma

Abstract

Purpose: Adoptive cell transfer, the infusion of large numbers of activated autologous lymphocytes, can mediate objective tumor regression in a majority of patients with metastatic melanoma (52 of 93; 56%). Addition and intensification of total body irradiation (TBI) to the preparative lymphodepleting chemotherapy regimen in sequential trials improved objective partial and complete response (CR) rates. Here, we evaluated the importance of adding TBI to the adoptive transfer of tumor-infiltrating lymphocytes (TIL) in a randomized fashion.

Patients and methods: A total of 101 patients with metastatic melanoma, including 76 patients with M1c disease, were randomly assigned to receive nonmyeloablative chemotherapy with or without 1,200 cGy TBI before transfer of tumor-infiltrating lymphcytes. Primary end points were CR rate (as defined by Response Evaluation Criteria in Solid Tumors v1.0) and overall survival (OS). Clinical and laboratory data were analyzed for correlates of response.

Results: CR rates were 24% in both groups (12 of 50 v 12 of 51), and OS was also similar (median OS, 38.2 v 36.6 months; hazard ratio, 1.11; 95% CI, 0.65 to 1.91; P = .71). Thrombotic microangiopathy was an adverse event unique to the TBI arm and occurred in 13 of 48 treated patients. With a median potential follow-up of 40.9 months, only one of 24 patients who achieved a CR recurred.

Conclusion: Adoptive cell transfer can mediate durable complete regressions in 24% of patients with metastatic melanoma, with median survival > 3 years. Results were similar using chemotherapy preparative regimens with or without addition of TBI.

Fig 1.

CONSORT diagram of enrollment. NMA, nonmyeloablative chemotherapy; TBI, total body irradiation; TIL, tumor-infiltrating lymphocyte.

Fig 2.

(A) Overall survival of patients randomly assigned to receive tumor-infiltrating lymphocytes (TILs) with nonmyeloablating chemotherapy (NMA; n = 51) versus those assigned to receive the same chemotherapy with the addition of total body irradiation (TBI) 1,200 cGy (1,200 TBI; n = 50). (B) Progression-free survival of those patients who received TIL with NMA (n = 51) versus NMA with 1,200 TBI (n = 48). (C) Spider plots depicting the pattern of changes in target lesions of patients receiving adoptive cell transfer. (D) Only one patient who achieved a complete response has recurred, as depicted by the diamond on the abscissa of the 1,200 TBI graph. The similar diamond on the NMA graph describes a patient who had an unconfirmed complete response who experienced progression with a new lesion; hence, the best response is partial response (PR). PD, progressive disease.

Fig A1.

Postprogression survival measured from date of progression to date of death (n = 50) or data cutoff date (n = 17) in patients who progressed after treatment with adoptive cell transfer. Groups were designated by type of therapy initiated without further data on response to that therapy. LTF, lost to follow-up or unable to obtain treatment details; PD-1, programmed death-1; Rx, treatment.

Fig A2.

Mean hematopoietic cell counts were transiently depressed in patients who received adoptive cell transfer, with a slightly longer period of neutropenia in patients who received total body irradiation 1,200 cGy TBI. Mean absolute counts were based on daily clinical CBCs. (A) Platelet counts, (B) absolute neutrophil counts, (C) absolute lymphocyte counts. NMA, nonmyeloablative chemotherapy.

Fig A3.

Peripheral blood was sampled before the start of chemotherapy for all 101 randomly assigned patients. (A) The median neutrophil-to-lymphocyte ratios (NLRs) were significantly different between response groups but without predictive value. (B) Baseline lactate dehydrogenase (LDH) values also had significantly different medians, and 34 patients had elevated values, including 5 who achieved complete response (CR). Color denotes arm of trial (blue, nonmyeloablative chemotherapy; gold, total body irradiation) and shape denotes response (▲, CR; ■, partial response [PR]; ○, no response [NR]). Lines denote median values, dashed line denotes upper limit of normal.

Fig A4.

(A) Autologous fresh tumor was available for use as targets in a coculture to measure interferon-gamma (IFN-γ) release by tumor-infiltrating lymphocyte (TIL) fragments for 74 patients. (B) Ability of HLA class I antibodies to block IFN-γ release was used as an indirect measure of CD8⁺ tumor recognition in the 65 patients with a positive screen. It was not uncommon to witness variation between fragments for a single patient. To demonstrate TIL heterogeneity in the 74 patients whose TILs were tested, we show (C) reactive fragments and (D) blockable fragments (number of positive wells/total number of wells tested (median/patient 24, range 6 to 36). Color denotes arm of trial (blue, nommyeloablative chemotherapy; gold, total body irradiation) and shape denotes response (▲, complete response [CR]; ■, partial response [PR]; ○, no response [NR]). Lines denote median values. ACT, adoptive cell transfer.

Fig A5.

Characteristics of administered tumor-infiltrating lymphocytes and evaluation of peak circulating lymphocytes in post-treatment days 0 to 9. Color denotes arm of trial (blue, nommyeloablative chemotherapy; gold, total body irradiation) and shape denotes response (▲, complete response [CR]; ■, partial response [PR]; ○, no response [NR]). Lines denote median values. (A) Number of CD3⁺ T cells in infusion bag in patients who achieved response (CR + PR) versus those who did not (NR). (B) Number CD8⁺ cells. (C) Percent of infused T cells that were CD3⁺CD45RA⁺CCR7− (T_EMRA). (D) Maximum absolute lymphocyte count as measured in the peripheral blood of patients in treatment days 0 to 9. OR, objective response.